Straightforward Synthesis of α-Chloromethylketimines Catalyzed by Gold(I). A Clean Way to Building Blocks

α-Chloromethylketimines have been obtained through a gold-catalyzed hydroamination of aromatic and aliphatic 1-chloroalkynes with aromatic amines by using equimolar amounts of both reagents. This procedure has allowed the preparation and spectroscopic characterization of α-chloromethylketimines for the first time with a high degree of purity, complete conversion, and atom economy. The synthetic usefulness of the methodology has been demonstrated with the preparation of β-chloroamines and indoles.

■ INTRODUCTION α-Monohalogenated imines are dielectrophilic compounds in which there has long been interest. 1 The reduction of these compounds provides β-haloamino derivatives, 2 the main entrance route for the synthesis of aziridines, 3 substances with interesting biological properties that are widely used as synthetic intermediates. 4 In addition, halogenated imines can be subjected to in situ cyclization to afford indoles, 5 piperidines, and other nitrogen-containing heterocycles. 6 Two strategies have been applied for the synthesis of halogenated ketimines: the electrophilic halogenation 7 of the corresponding imine in a process similar to the halogenation of ketones and the condensation of a monohalogenated ketone with an amine (Scheme 1). In the first case, the low regioselectivity and the formation of per-halogenated or unstable compounds make this procedure unsuitable for the monochlorination of simple ketimines. The second route, usually catalyzed by molecular sieves 8 or TiCl4, 9 is less effective in the case of hindered amines or when ketones are used instead of aldehydes. In addition, the condensation reaction requires in most cases the use of a large excess of one of the reactants. Due to their facile hydrolysis, purification is a major problem and prevents the isolation of α-halogenated ketimines. For this reason, they have never been properly characterized by NMR. Thus, these species are used in situ in the presence of large amounts of starting materials and side products that complicate subsequent transformations. 5,6,8,9 The synthetic routes for α-chloroketimines described so far cannot be considered general or satisfactory in any instance. Therefore, the design of a general and clean way to prepare these versatile building blocks is necessary. With this aim, we have developed a new strategy by using 1-chloroalkynes as precursors and Au(I) catalysis (Scheme 1). 1-Chloroalkynes are readily available compounds whose usefulness in synthesis has been widely demonstrated. 10 In this context, Xiang, He, and coworkers 11 reported the synthesis of α-halomethylketones in the gold-catalyzed hydration of 1-haloalkynes. On the contrary, since the pioneering work of Tanaka, 12 the intermolecular hydroamination of alkynes has been highlighted as one of the best alternatives for the synthesis of conventional imines and enamines. 13 Interesting advantages of organic gold derivatives are the compatibility with the presence of different functional groups, the very low air sensitivity, and the stability to βelimination of these compounds. 14 Different Au complexes and nanoparticles have been used in the reaction of alkynes with amines 15 and other N-nucleophiles 16 with excellent results, but to the best of our knowledge, none of the methodologies described has been used to address the preparation of halogenated imines in spite of their synthetic value.
In this paper, we describe the regioselective Markovnikov hydroamination of 1-chloroalkynes to afford α-chloroimines in high yields under mild reaction conditions.
These selected conditions were used for the reaction of alkyne 1a with a series of primary amines 2a−h to yield the corresponding chlorinated imines 3aa−ah, respectively. Reaction mixtures were heated until complete conversion of chloroalkyne 1a had been achieved followed by GC analysis. Yields determined by NMR and reaction times are shown in Table 2.
Reactions proceeded smoothly to the formation of both Z and E imines together with trace amounts of the corresponding enamines. Manipulation of reaction crudes was limited to toluene evaporation and addition of the deuterated solvent and standard. Any other purification procedure led to extensive hydrolysis of reaction products. Moreover, even substitution of a solvent for deuterated chloroform under inert conditions provoked the partial (2−7%) hydrolysis of cloromimines 3 into α-chloromethylketone 4a. Yields were determined by 1 H NMR using 1,1,2,2-tetrachloroethane as the internal standard. The NMR spectra corresponding to the crude reaction products can be found in the Supporting Information.
The noteworthy efficiency of this procedure is demonstrated by the impressive result obtained with the strongly hindered 2,6diisopropylaniline (2b). It must be pointed out that imine 3ab can be hardly prepared through condensation reactions. The hydroamination reaction also tolerates the presence of both electron-donating (3ac) and electron-withdrawing (3ad) groups on the aniline aromatic ring. In the case of the strong withdrawing substituent nitro group (3ae), the product was formed in high yield, although the corresponding chloroenamines were obtained preferentially over the imine tautomers. Additionally, the yield is not affected by the presence of free hydroxy groups on the substrates as observed in 3af. Unfortunately, the presence of more basic nitrogen atoms in the amine counterpart like those of pyridine 2g or aliphatic amine 2h inhibits the transformation, and chloroalkyne 1a was recovered unreacted probably due to the strong coordination of the amine with the gold catalyst.
During a second step, we explored the reactivity of different 1chloroalkynes (1b−f) with aniline (2a), and the results are summarized in Table 3. Excellent to very good yields were obtained in all cases, except for chloroalkyne 2f, for which the presence of a pyridine again inhibited the reaction. The addition of 1 equiv of TfOH to avoid catalyst poisoning 17 resulted in the formation of a complex reaction mixture. Chloroalkyne 2b with the bulky mesityl substituent needed 15 h to complete the reaction, and the elusive imine 3ba could be obtained in 97% yield.
Aliphatic chloroalkyne 1e gave the expected product as a mixture of different imines and the corresponding enamines (see the Supporting Information). In this case, 22% hydrolysis of the  product could not be avoided due to the higher sensitivity of 3ea to traces of water. When hindered amine 2b was used for the hydroamination reaction of aliphatic alkyne 1e, the expected chloroimine 3eb was obtained in 98% yield as a 65:35 Z/E mixture of diastereomers (Scheme 2). In this case, enamines were observed only in traces. Encouraged by the remarkable results obtained for encumbered chloroimines 3ab, 3ba, and 3eb, we attempted to synthesize the challenging chloroimine 3bb under our standard conditions. To our delight, the expected chloroimine 3bb was formed in 98% yield after 15 h at 120°C with just 1 mol % activated IPrAuCl catalyst, as one can see on the 1 H NMR spectrum of the crude reaction mixture ( Figure 1).
Additionally, we checked the viability of the gold-catalyzed hydroamination reaction for all possible combinations of electron-withdrawing and electron-donating substituents at the para position of the chloroalkyne and amine counterparts. As one can interpret from the results shown in Table 4, catalyst effectiveness is maintained in any case. The presence of electrondonating groups on the aniline moiety (2c) increases the nucleophilicity of the nitrogen atom but also the coordinating ability to the catalyst, leading to results similar to those of aniline 2a. In fact, a longer reaction time was required for the preparation of chloroimine 3cc that joins electron-donating groups in both starting materials. In addition, it was observed that products derived from chloroalkyne 1c are more prone to hydrolysis.
We studied the formation of chloroimine 3da through NMR spectroscopy to assess if the Z/E stereoselectivity observed for the gold-catalyzed hydroamination reactions is a consequence of the catalyst activity or is due to tautomeric equilibrium. For safety reasons, the temperature of the reaction was decreased to 80°C. Consequently, the catalyst amount was doubled to maintain the reaction rate. Figure 2 shows the evolution of the Reaction conditions: 1b−f (0.5 mmol), 2a (0.5 mmol), IPrAuCl (5 μmol), NaBArF (7.5 μmol), toluene (1.2 mL). b Yields determined by 1 H NMR using 1,1,2,2-tetrachloroethane as the internal standard. c To achieve complete conversion of 1e, 2 mol % IPrAuCl and 3 mol % NaBArF had to be used. d In the case of alkyne 1f, starting materials were recovered unreacted.
Scheme 2. Synthesis of α-Chloroimine Tautomers 3ea and 3eb  Chloroenamines are highly reactive interesting synthetic intermediates that have been prepared through TiCl 4 -catalyzed condensation of the corresponding α-chloroketone with an excess of secondary amine. 18 Due to the limitations associated with this procedure, only chloroenamines derived from aliphatic amines have been synthesized. We tested the performance of our catalytic system on the hydroamination reaction of chloroalkyne 1a with the secondary aromatic amines 5a−e under our standard conditions ( Table 5). The expected chloroenamine 6aa from Nmethylaniline was formed in excellent 90% yield exclusively in the E configuration (see the Supporting Information). The reaction tolerates the presence of electron-donating (6ab) and electron-withdrawing (6ac) groups on the aromatic ring of the amine and on the alkyne (6de), although for electron rich secondary amine 5b some chloroalkyne remained unreacted under the standard reaction conditions. The methyl group on the nitrogen atom can be replaced by a longer alkyl chain (6ad) or a second aromatic ring (6de) without an important loss of yield. These results open a way to the synthesis of a new family of aromatic chloroenamines that have not been accessible to date.
The synthetic usefulness of this procedure was evaluated through the development of two derivatization procedures based on one-pot, two-step syntheses. First, crude chloroimines 3aa, 3ba, and 3ea were directly subjected to palladium-catalyzed cyclization to afford indoles 7 (Table 6). The results obtained with this selection of chloroimines show the power of this methodology for preparing indoles presenting bulky or aliphatic substituents, arduous to synthesize through other pathways such as condensation 5 or cross-coupling. 19 Additionally, a procedure for the direct reduction to βchloroamines has been assayed. These interesting compounds are important intermediates for the preparation of aziridines. 3 Their syntheses are especially complicated in the case of substrates with bulky substituents. Once complete conversion of the corresponding chloroalkyne into the imine was achieved, toluene was replaced by methanol and NaBH 3 CN added as the reductant. This procedure was applied to a selection of examples. The yields obtained of the crude chloroamines (8) are listed in Table 7.
In conclusion, we have developed a new catalytic procedure for the synthesis of α-chloromethylketimines with full atom economy. The hydroamination reaction takes place with equimolar amounts of chloroalkynes and aromatic amines. The appropriate gold catalyst at just 1 mol % is enough to reach complete conversions and allows the preparation of these interesting synthetic intermediates in a degree of purity not yet achieved. The scope of this method has been extended to the use of secondary amines for the preparation of the elusive  Table 5. Gold-Catalyzed Chloroenamine Synthesis a a Reaction conditions: 1a or 1e (0.5 mmol), 5a−e (0.5 mmol), IPrAuCl (5 μmol), NaBArF (7.5 μmol), toluene (1.2 mL). b Yields determined by 1 H NMR using 1,1,2,2-tetrachloroethane as the internal standard. c 19% of unreacted chloroalkyne 1a was recovered.  The Journal of Organic Chemistry pubs.acs.org/joc Article chloroenamines. To assess the usefulness of this synthetic procedure, two significant kinds of building blocks, β-chloroamines and indoles, have been cleanly prepared through direct methods.

■ EXPERIMENTAL SECTION
General Experimental Details. Chloromethylimines are products that are very sensitive to hydrolysis. All transformations have been performed using common Schlenk techniques or in a glovebox. Toluene, toluene-d 8 , and THF have been dried with sodium prior to use. Deuterated chloroform and liquid amines have been distilled from CaH 2 prior to use. NMR analyses have been performed in a Bruker AvanceIII 300 spectrometer, a Bruker AV400 spectrometer, or a Bruker Neo500 spectrometer. NMR data have been processed using MestReNova or TopSpin. Residual signals of deuterated solvents have been used as internal references (CDCl 3 at 7.26 ppm in 1 H NMR and 77.16 ppm in 13 C NMR and toluene-d 8 at 2.08 and 20.43 ppm for methyl group in 1 H NMR and 13 C NMR, respectively). IR spectra have been recorded on a Thermo Scientific Nicolet iS10 instrument and processed with Omnic. IR band frequencies have been rounded to 1 cm −1 . GC-MS analyses have been performed with an Agilent 5977A instrument equipped with a 30 m × 0.25 m × 0.25 μm HP-5ms ui column. HRMS (+ESI) analyses have been performed in an AB SCIEX TripleTOF 5600 LC/MS/MS system, and data have been processed using PeakView. Elemental analyses have been performed in a Thermofisher Flashmart Eager 200 instrument.
Gold-Catalyzed Hydroamination Reactions. IPrAuCl (3 mg, 5 μmol, 1 mol %) and NaBArF (6.6 mg, 7.5 μmol, 1.5 mol %) were weighed in a glovebox and introduced into an ampule provided with a J. Young valve. Once at the Schlenk line, the mixture of solids was suspended in 1.2 mL of toluene and stirred for 10 min at room temperature before the addition of amine (0.5 mmol) followed by chloroalkyne (0.5 mmol). The ampule was closed and heated to 120°C for the indicated time in an oil bath (Tables 2−4). After the mixture had cooled to room temperature, the solvent was evaporated, the crude mixture was dissolved in 1.5 mL of CDCl 3 , and 1,1,2,2-tetrachloroethane was added as the internal standard. The resulting solution was analyzed via NMR and HRMS (+ESI).